PHF6 is a key regulator of normal human hematopoiesis by modulating NOTCH1 signaling activity
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ABSTRACT:
PROVIDER: PRJNA338287 | ENA |
REPOSITORIES: ENA
Similar Datasets
Project description:This SuperSeries is composed of the SubSeries listed below.
2020-12-01 | GSE85373 | GEO
Project description:Plant homeodomain finger gene 6 (PHF6) encodes a 365-amino-acid protein containing two plant homology domain fingers. Germline mutations of human PHF6 cause Börjeson–Forssman–Lehmann syndrome, a congenital neurodevelopmental disorder. Loss-of-function mutations of PHF6 are detected in patients with acute leukemia, mainly of T cell lineage and in a small proportion of myeloid lineage. The functions of PHF6 in physiological hematopoiesis and leukemogenesis remain incompletely defined. To address this question, we generated a conditional Phf6 knockout mouse model and investigated the impact of Phf6 loss on the hematopoietic system. We found that Phf6 knockout mice at 8-week age had reduced numbers of CD4+ and CD8+ T cells in the peripheral blood compared to the wild-type littermates. There were decreased granulocyte-monocytic progenitors but increased Lin-c-Kit+Sca-1+ (LSK) cells in the marrow of young Phf6 knockout mice. Functional studies including competitive repopulation unit and serial transplantation assays revealed an enhanced reconstitution and self-renewal capacity in Phf6 knockout hematopoietic stem cells (HSCs). Aged Phf6 knockout mice had myelodysplasia-like presentations including decreased platelet counts, megakaryocyte dysplasia, and enlarged spleen related to extramedullary hematopoiesis. Moreover, we found that Phf6 loss lowered the threshold of NOTCH1-induced leukemic transformation at least partially through increased leukemia-initiating cells. Transcriptome analysis on the restrictive rare HSC subpopulations revealed upregulated cell cycling and oncogenic functions, with alteration of expression of key genes in those pathways. In summary, our studies demonstrate the in vivo crucial roles of Phf6 in physiological and malignant hematopoiesis.
2019-08-21 | GSE129465 | GEO
Project description:Analysis of the mutational landscape of various hematological malignancies has shown that key regulators implicated in lineage commitment and differentiation are frequently implicated in leukemic transformation. In T-cell acute lymphoblastic leukemia, the role of various oncogenic and tumor suppressing transcription factors has been investigated. More recently, an exceptional high prevalence of mutations affecting epigenetic modifiers in T-ALL has also been noted. In order to understand the exact contribution of such lesions to normal differentiation and oncogenic transformation, further functional characterization of this subclass of proteins is warranted. PHF6 is one of these key epigenetic players, which was described as a frequently mutated and deleted novel tumor suppressor in T-ALL. In a first step towards unraveling the role of PHF6 in normal and malignant hematopoiesis, we characterized the function of PHF6 in both normal T-cell differentiation and other hematopoietic lineages as a prelude to understand its contribution to leukemogenesis. Here, we show for the first time that PHF6 controlled epigenetic regulation positively controls a NOTCH1 gene signature and the effects observed on T-lineage differentiation seem to be additive with Notch1. In this study, we show for the first time that PHF6 is a master regulator of early hematopoietic differentiation along the T-cell, B-cell, myeloid and NK-cell lineages.
2020-12-01 | GSE85372 | GEO
Project description:Analysis of the mutational landscape of various hematological malignancies has shown that key regulators implicated in lineage commitment and differentiation are frequently implicated in leukemic transformation. In T-cell acute lymphoblastic leukemia, the role of various oncogenic and tumor suppressing transcription factors has been investigated. More recently, an exceptional high prevalence of mutations affecting epigenetic modifiers in T-ALL has also been noted. In order to understand the exact contribution of such lesions to normal differentiation and oncogenic transformation, further functional characterization of this subclass of proteins is warranted. PHF6 is one of these key epigenetic players, which was described as a frequently mutated and deleted novel tumor suppressor in T-ALL. In a first step towards unraveling the role of PHF6 in normal and malignant hematopoiesis, we characterized the function of PHF6 in both normal T-cell differentiation and other hematopoietic lineages as a prelude to understand its contribution to leukemogenesis. Here, we show for the first time that PHF6 controlled epigenetic regulation positively controls a NOTCH1 gene signature and the effects observed on T-lineage differentiation seem to be additive with Notch1. In this study, we show for the first time that PHF6 is a master regulator of early hematopoietic differentiation along the T-cell, B-cell, myeloid and NK-cell lineages.
2020-12-01 | GSE85371 | GEO
Project description:Loss-of-function mutations Phf6 occur frequently in both adult and pediatric T-cell Acute Lymphoblastic Leukemia (T-ALL). Although Phf6 is widely expressed, little is known about its proposed function as epigenetic regulator and tumor suppressor. To address the role of Phf6 in the leukemia development, here we analyze by RNAseq the gene expression profiles of isogenic Phf6 wild type and Phf6 knockout leukemia cells transformed by overexpression of an oncogenic mutant form of the NOTCH1 receptor.
2019-07-31 | GSE117165 | GEO
Project description:Analysis of the mutational landscape of various hematological malignancies has shown that key regulators implicated in lineage commitment and differentiation are frequently implicated in leukemic transformation. In T-cell acute lymphoblastic leukemia, the role of various oncogenic and tumor suppressing transcription factors has been investigated. More recently, an exceptional high prevalence of mutations affecting epigenetic modifiers in T-ALL has also been noted. In order to understand the exact contribution of such lesions to normal differentiation and oncogenic transformation, further functional characterization of this subclass of proteins is warranted. PHF6 is one of these key epigenetic players, which was described as a frequently mutated and deleted novel tumor suppressor in T-ALL. In a first step towards unraveling the role of PHF6 in normal and malignant hematopoiesis, we characterized the function of PHF6 in both normal T-cell differentiation and other hematopoietic lineages as a prelude to understand its contribution to leukemogenesis. Here, we show for the first time that PHF6 controlled epigenetic regulation positively controls a NOTCH1 gene signature and the effects observed on T-lineage differentiation seem to be additive with Notch1. In this study, we show for the first time that PHF6 is a master regulator of early hematopoietic differentiation along the T-cell, B-cell, myeloid and NK-cell lineages.
2020-12-01 | GSE85370 | GEO
Project description:Analysis of the mutational landscape of various hematological malignancies has shown that key regulators implicated in lineage commitment and differentiation are frequently implicated in leukemic transformation. In T-cell acute lymphoblastic leukemia, the role of various oncogenic and tumor suppressing transcription factors has been investigated. More recently, an exceptional high prevalence of mutations affecting epigenetic modifiers in T-ALL has also been noted. In order to understand the exact contribution of such lesions to normal differentiation and oncogenic transformation, further functional characterization of this subclass of proteins is warranted. PHF6 is one of these key epigenetic players, which was described as a frequently mutated and deleted novel tumor suppressor in T-ALL. In a first step towards unraveling the role of PHF6 in normal and malignant hematopoiesis, we characterized the function of PHF6 in both normal T-cell differentiation and other hematopoietic lineages as a prelude to understand its contribution to leukemogenesis. Here, we show for the first time that PHF6 controlled epigenetic regulation positively controls a NOTCH1 gene signature and the effects observed on T-lineage differentiation seem to be additive with Notch1. In this study, we show for the first time that PHF6 is a master regulator of early hematopoietic differentiation along the T-cell, B-cell, myeloid and NK-cell lineages.
2020-12-01 | GSE85369 | GEO
Project description:The plant homeodomain 6 gene (PHF6) is frequently mutated in human T-cell acute lymphoblastic leukemia (T-ALL); however, its specific functional role in leukemia development remains to be established. Here, we show that loss of PHF6 is an early mutational event in leukemia transformation. Mechanistically, genetic inactivation of Phf6 in the hematopoietic system enhances hematopoietic stem cell (HSC) long-term self-renewal and hematopoietic recovery after chemotherapy by rendering Phf6 knockout HSCs more quiescent and less prone to stress-induced activation. Consistent with a leukemia-initiating tumor suppressor role, inactivation of Phf6 in hematopoietic progenitors lowers the threshold for the development of NOTCH1-induced T-ALL. Moreover, loss of Phf6 in leukemia lymphoblasts activates a leukemia stem cell transcriptional program and drives enhanced T-ALL leukemia-initiating cell activity. These results implicate Phf6 in the control of HSC homeostasis and long-term self-renewal and support a role for PHF6 loss as a driver of leukemia-initiating cell activity in T-ALL.
2021-06-23 | GSE178739 | GEO
Project description:Here we identify the genome-wide occupancy of PHF6 in T-ALL cells. Human T-ALL cells were cross-linked with formaldehyde for 20 min. DNA was enriched by chromatin immunoprecipitation (ChIP) and analyzed by Solexa sequencing. A sample of whole cell extract (WCE) was sequenced and used as the background to determine enrichment. ChIP was performed using an antibody against total PHF6 (Bethyl A301-451A). This represents the ChIP-seq portion of this dataset.
2014-04-01 | E-GEOD-45864 | biostudies-arrayexpress
Project description:E18 embryonic rat cortical neurons cultured in vitro are infected with lentivirus expressing control or PHF6shRNA-2, and harvested 5 days after infection pLL3.7 lentivirus expressing control or PHF6shRNA-2 was generated in 293T cells and concentrated using ultracentrifuge. In vitro cultured cortical neurons were infected and RNA was harvested 5 days after infection. PHF6 knockdown was validated by QPCR before sample was processed for microarray analysis.
2013-08-01 | E-GEOD-45953 | biostudies-arrayexpress